The most recent report from the Research Advisory Committee on Gulf War Veterans' Illnesses stated that Identification of objective measures that distinguish Veterans with Gulf War Illness from Healthy Veterans including studies that utilize new technologies (proteomic...metabolomic methods) capable of identifying unique molecular characteristics of Gulf War Illness, and of illness and exposure subgroups was one of the Highest Priority areas for Gulf War Research. In this proposal we will address this critical need by using state-of-the-art omic technology (proteomic, lipidomic and metabolomic) to comprehensively characterize plasma molecules responding to mouse exposure to Gulf War (GW) agents, such as pesticides and the anti-nerve gas agent pyridostigmine bromide. We will focus on mouse models of GW-agent induced central nervous system (CNS) dysfunction. Plasma profiles will be compared across different mouse models, different timepoints and different clinical presentations in order to identify biological functions correlating with CNS dysfunction that are specifically modulated following GW-agent exposure. With our clinical collaborators at the Boston and Bronx VA hospitals we will recruit Veterans with GWI, healthy GW Veterans, and GW-era Veterans who were not deployed to the Gulf. We will similarly profile their plasma, and will compare the profiles across clinical subgroups and use the results from the mouse studies to identify the differentially represented biological functions of most significance to GWI CNS dysfunction. We will then explore the development of a plasma biomarker panel by using targeted omic investigations and screening an additional GW Veterans population to qualify the biomarker findings from the discovery phase by determining the reproducibility of the diagnostic specificity and sensitivity of the candidate biomarkers under investigation. This novel and innovative proposal addresses many of the outstanding needs pertaining to issues related to GWI, a) diagnostic biomarkers, b) differences in biological responses due to genetic heterogeneity, c) personalized medicine. Biomarkers may also be identified which can be used as surrogates for evaluation of therapeutic efficacy. Furthermore, this work provides a template for subsequent analyses of additional samples from existing and future clinical collaborations. We anticipate that our study can provide the foundation for a nationwide plasma biomarker discovery program for Gulf War Veterans Illness.